B210611

Quest Journals Journal of Research in Pharmaceutical Science Volume 2 ~ Issue 1 (2014) pp: 06-11 ISSN(Online) : 2347-2995 www.questjournals.org Research Paper

Local drug delivery in Periodontics: A tactical entreaty Dr Vaishali Ashtaputre1, Dr Mrinal Limaye2 1

Professor & Head, Department of Periodontology Post graduate student Department of Periodontology C.S.M.S.S Dental college & hospital, Aurangabad, Maharashtra 2

Received 20 January, 2014; Accepted 31 January, 2014 Š The author(s) 2013. Published with open access at www.questjournals.org ABSTRACT: - Periodontitis is a silent disease. It is an inflammatory disease of the supporting tissues of the teeth caused by groups of specific microorganisms. The periodontal diseases are major cause of tooth loss for population irrespective of sex, age and races. Various treatment modalities have been tried to combat such diseases. Amidst it the most commonly employed are professional scaling polishing along with plaque control measures. In some cases, owing to limited success local applications of some antibacterial agents either by topical application or local drug delivery in periodontal pockets has been evaluated. Periodontal pockets provide natural reservoir bathed by gingival crevicular fluid that is easily accessible for the insertion of a delivery device. Controlled release delivery of antimicrobials directly into periodontal pockets has received eminent interest and appears to hold a level headed promise in periodontal therapy. It does not substitute conventional mechanical debridement but acts as an adjunct to it. The periodic use of local drug delivery in improving gingival and periodontal condition, would allow better control and management of periodontal disease. Literature reviews various drugs used for many decades in the field of Periodontology, prognosticating boosting results. This review article sheds light on the concept of local drug delivery in Periodontics and emphasizes on various drug systems available to date and rationales of using those antibacterial drugs systems through local delivery into the periodontal pockets.

Keywords: - Inflammatory, local drug delivery, Periodontitis, periodontal pocket, scaling and polishing I.

INTRODUCTION

Gingival and periodontal diseases, in their various forms, have afflicted humans since the dawn of history. Periodontal diseases are considered infections of the periodontium, owing to the bacterial etiology, an immune response, and tissue destruction.[1] In 1976 LĂśesche et al. proclaimed the specific plaque hypothesis, suggesting that specific bacteria caused specific forms of periodontal diseases.[1] Since then newer treatment strategies, aiming primarily at suppression or elimination of specific periodontal diseases have been established.

Putative pathogens associated with periodontal diseases are susceptible to a variety of antiseptics and antibiotics.[2, 3] Methods employed to convey antimicrobial agents into periodontal pockets have included rinsing, irrigation, systemic administration, and local application using sustained and controlled delivery devices. Success of any drug delivery system designed to target periodontal infections depends upon its ability to deliver the antimicrobial agents to the base of pocket, at a bacteriostatic or bactericidal concentration. [4] It must also facilitate retention of the medicament long enough to ensure an efficacious result. [4] Since local drug delivery can achieve the above requirements, it was thought important to critically assess the ability of these treatment methods to accomplish periodontal health. Numerous local drug transport products have undergone preliminary assessments. [3, 5, 6] but only a few methods have been evaluated in several studies. This paper addresses the potential efficacy of various delivery systems being used in Periodontics.

II.

LOCAL DELIVERY AGENTS

The choice of the antimicrobial agents in periodontal diseases must be based on the bacterial etiology of the infection. There are distinct phases in a periodontal treatment plan where a dental practitioner can use a sustained release device. It can be used as an adjunct to scaling and root planing and for periodontal maintenance therapy. It has been observed that the local route of drug delivery can attain 100-fold higher concentrations of an antimicrobial agent in subgingival sites compared with a systemic drug regimen thereby *Corresponding Author: Dr Vaishali Ashtaputre

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Local drug delivery in periodontics: tactical entreaty reducing the total patient dose by over 400 fold avoiding development of drug-resistant at non oral body sites.

[7]

III. VARIOUS AGENTS USED 3.1. Povidone-iodine The value of diluted povidone-iodine solution (final concentration 0.05% free iodine) irrigation of periodontitis lesions as an adjunct to subgingival debridement revealed reduction in gingival inflammation and 2 mm or more in gain of clinical attachment; enhanced healing pertaining to better suppression over periopathogens. [8, 9] 3.2. Tetracycline In 1979 Goodson et al first proposed the concept of controlled delivery in the treatment of periodontitis. [4] Tetracycline are a group of closely related bacteriostatic antimicrobials.

Tetracycline-HCl in vitro displays substantivity to dentin tooth surfaces, and maintains its antimicrobial activity upon desorption [10, 11.] The first delivery devices involved hollow fibers of cellulose acetate filled with tetracycline. [12] 3.2.1. Fibers: The ACTISITE tetracycline fibres have been approved for the treatment of adult periodontitis by the United States Food and Drug Administration (FDA). These are non-resorbable biologically inert, safe, plastic copolymer (ethylene and vinyl-acetate) loaded with 25% w/w tetracycline HCI powder packaged as a thread of 0.5 mm in diameter and 23 cm in length. It maintains constant concentrations of active drug in the crevicular fluid in excess of 1000 μg/ml for a period of 10 days. [13] Following application of tetracycline fibres a definite reduction in the subgingival microbiota has been observed. [14] Bio-resorbable form of fibre commercially available as PERIODONTAL PLUS AB offers the advantage of no second appointment for removal as it biodegrades within 7 days.

3.2.2. Gel: Noteworthy results were seen with Tetracycline-Serratiopeptidase-Containing Periodontal Gel Formulation along with scaling and root planing. [15] Bio erodible Injectable Poly (ortho ester) for Tetracycline Controlled Delivery formulations loaded with tetracycline 10% or 20% showed complete in vitro degradation concomitant with drug release. [16] In general, tetracycline helped in improvement of periodontal parameters.

3.3 Subgingival Doxycycline Doxycycline is a bacteriostatic agent and has the ability to downregulate MMP’s a family of zinc dependent enzymes that are capable of degrading a variety extracellular matrix molecules including collagens.

[17] The only FDA approved 10% Doxycycline in a gel system ATRIDOX (42.5 mg Doxycycline) is a subgingival controlled-release product composed of a 2 syringe mixing system. Doxycycline levels in GCF peaked to 1,500 - 2000 μg/ml in 2 hours following treatment with ATRIDOX. These levels remained above 1000 μg/ml through 18 hours, at which time the levels began to decline gradually. Local levels of Doxycycline have been found to remain well above the minimum inhibitory concentration for periodontal pathogens (6.0μg/ml) through Day 7. Approximately 95% of the polymer is bio absorbed or expelled from the pocket naturally within 28 days. [18] Several studies have reported probing depth reduction and gaining clinical attachments. [19, 20] 3.4. Subgingival Minocycline Local delivery of minocycline, a bacteriostatic antibiotic has been tried clinically via in three different modes i.e. film, microspheres, and ointment. [21, 22] 3.4.1. Film: Ethyl cellulose film containing 30% of Minocycline were tested as sustained release devices. The results indicated that the use of this device may cause complete eradication of pathogenic flora from the pocket after 14 days. [23] 3.4.2. Microsphere: A new, locally delivered, sustained release form of minocycline microspheres (ARESTIN) for subgingival placement is available. The 2% minocycline is encapsulated into bio-resorbable microspheres (20-60μm in diameter) in a gel carrier and has resorption time of 21 days. Gingival crevicular fluid hydrolyses the polymer and releases minocycline for a period of 14 days or longer before resorbing completely. [23] 3.4.3. Ointment: Minocycline ointment is a bio-absorbable sustained delivery system consisting of 2% minocycline hydrochloride in a matrix of hydroxyethyl-cellulose, aminoalkyl-methacrylate, triacetine and *Corresponding Author: Dr Vaishali Ashtaputre

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Local drug delivery in periodontics: tactical entreaty glycerine. Dentomycin (2% Minocycline gel) has received regulatory approval for the treatment of periodontitis in the European Union. In Japan it is commercially available with name Periocline. The concentration of minocycline in the periodontal pocket is about 1300μg/ml, 1 hr after single topical application of 0.05 ml ointment (1mg of minocycline) and is reduced to 90μg/ml after 7 hrs. Results have shown that the combination of ointment with scaling and root planing was significantly better than scaling and root planing alone in pockets > 7mm. [24] 3.5 Subgingival Chlorhexidine The use of chlorhexidine as an antifungal and antibacterial agent has been well established.

Chlorhexidine is used in mouth rinses and is highly recommended in the hygiene phase of treatment as an adjunct to tooth brushing. The major application has been for the control of dental plaque and gingivitis. Its mechanism of action relates to reduction in pellicle formation, alteration of bacterial adherence to teeth and an alteration of bacterial cell walls causing lysis. Its antibacterial action is due to an increase of the cellular membrane permeability followed by the coagulation of intracellular cytoplasmic macromolecules. Because chlorhexidine is highly cationic, it exhibits high substantivity. The long term efficacy of chlorhexidine on the periodontal pocket flora is dependent on the duration of exposure. However, intracrevicular irrigation of the periodontal pocket with chlorhexidine has only a short lived effect on the pocket flora. [25] Chlorhexidine is available in the form of mouthrinses, Gels, varnishes, and chip to be used as a local drug delivery agent for the treatment of periodontal diseases.

3.5.1 Periochip: 2.5 mg Chlorhexidine Gluconate PerioChip, the controlled subgingival delivery of chlorhexidine gluconate, is a small, orange-brown, tombstone-shaped chip (4.0 x 0.5 x 0.35mm) in a biodegradable matrix of hydrolyzed gelatine and has been approved by FDA. Studies with Perio Chip showed reduction in the numbers of the putative periodontopathic organisms after placement of the chip. No overgrowth of opportunistic organisms or other adverse changes in the oral microbial ecosystem were noted. Perio Chip releases chlorhexidine in vitro in a biphasic manner, initially releasing approximately 40% of the chlorhexidine within the first 24 hours, and then releasing the remaining chlorhexidine in an almost linear fashion for 7–10 days. Several studies compared the efficacy of scaling/root planing and combined therapy employing Chlorhexidine chips. Results indicating the number of sites with probing depth reduction were greater with combined therapy. [26, 27] 3.5.2 Periocol-CG: Periocol CG is prepared by incorporating 2.5mg chlorhexidine from a 20% chlorhexidine solution in collagen membrane. Size of the chip is 4x5 mm and thickness is 0.25 - 0.32 mm and 10 mg wt. Collagen is a natural protein, which is chemotactic for fibroblasts, enhances fibroblast attachment via its scaffold like fibrillar structure and stimulates platelet degranulation, thereby accelerating fibers and clot attachment. It has been shown to resorb after 30 days; however their coronal edge degrades within 10 days. [28] 3.5.3.Chlo-Site: Chlo-Site is an agent containing 1.5% chlorhexidine of xanthan type (Ghimas Company, Italy).

Xanthan gel is a saccharide polymer, which constitutes of a three-dimensional mesh mechanism, which is biocompatible with chlorhexidine. The gel gets vanished from the pocket within l0-30 days of injection and effective concentration of chlorhexidine against microorganismsis established for at least 15 days in the region.

Both chlorhexidine and gel matrix are mucoadhesive so that they stick inside the pockets and are not easily washed out by gingival fluid or saliva. It degrades spontaneously at the site of application, is well tolerated and is efficient in treatment of periodontal pockets & periimplantitis. [28] 3.6. Subgingival Metronidazole Metronidazole has often been chosen because of its selective efficacy against obligate anaerobes. It acts by inhibiting DNA synthesis. After application of Elyzol 25% dental gel, Metronidazole concentrations of above100 μ/ml were measurable in the periodontal pocket for at least 8 hours and concentrations above 1 μ/ml were found at 36 hours. [29] A topical medication ELYZOL contains an oil-based Metronidazole 25% dental gel (glyceryl mono-oleate and sesame oil). It is applied in viscous consistency to the pocket, where it is liquidized by the body heat and then hardens again, forming crystals in contact with water. One study suggested better result when combined therapy was employed for probing depth reduction. [30]

IV. ANTIBIOTIC SELECTION The most effective therapy matches the putative pathogen with an appropriate drug. Tetracyclines have often been administered to non-responsive patients, as they are broad spectrum and are effective against many periodontal pathogens including A. actinomycetemcomitans (A. a) [2, 3] However, some investigations have stated that tetracycline might not be effective in doing so. [31, 32] Currently, for A.a infections multiple drugs

*Corresponding Author: Dr Vaishali Ashtaputre

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Local drug delivery in periodontics: tactical entreaty such as amoxicillin and clavulanate potassium or Ciprofloxacin plus metronidazole have been employed. [3] It is apparent that no single drug is the universal drug of choice.

V. SELECTION OF APPROPRIATE DRUG CONCENTRATIONS FOR LOCAL DELIVERY Bacteria associated with periodontal diseases are usually found in biofilms requiring considerably higher concentrations of drugs to kill bacteria in biofilms. [33, 34] In order to combat dentomicrobial infections, different antimicrobials at a variety of concentrations need to be tested against a panel of suspected pathogens.

[34] Currently, the best way to determine the ideal drug concentrations is to compare in vitro and in vivo results.

VI.

FUTURE PERSPECTIVES

Eradicating microorganisms from the periodontal pocket is a crucial task in treating periodontitis. For treating periodontal diseases targeting of an anti-infective agent to infection sites with effective levels for a sufficient time while concurrently evoking minimal or no side effects is needed. [35] Novel therapeutic agents are being improvised in the arena of local drug delivery system to ensure maximum benefit.

6.1. Drugs for osseous defects 6.1.1. Alendronate: Alendronate a novel bisphosphonate is a very potent inhibitor of bone resorption.

Its net effect might be explained by its inhibition of osteoclasts thus affecting the bone maturation and remodelling thereby inducing bone formation. Systemically administed bisphosphonates leads to gastrointestinal disturbances but Local drug delivery avoids most of these problems, by limiting the drug to the target site; also allowing a local concentration at a much higher level than possible by systemic route. [36, 37] 6.1.2. Simvastatin: Statins like simvastatin (SMV), lovastatin, are specific competitive inhibitors of 3hydroxy-2-methyl-glutaryl coenzyme A (HMGCoA) reductase, widely used to lower cholesterol, and for treating hyperlipidemia and arteriosclerosis. Statins modulate bone formation by increasing the expression of bone morphogenetic protein-2, inflammation, and angiogenesis. Various studies showed that SMV assists in bone regeneration as well as the anti-inflammatory effect when delivered or applied locally. [38, 39] 6.2. Okade and co-workers developed a new sub gingival release delivery system (PT-01) containing Ofloxacin for sub gingival therapy and found it to be effective in the reducing plaque scores and bleeding scores. [40] 6.3. Clarithromycin gel: A clinical study investigating the efficacy of adjunctive use of subgingivally delivered 0.5 % clarithromycin to scaling for treating chronic periodontitis smoker subjects; saw that the adjunctive use of the drug reduced the post operative gingival and periodontal parameters and enhanced the clinical outcome. This product is still under investigation and yet to be patented. [41] 6.4. Herbs for periodontitis: Various herbal formulations like Aloe Vera, Bloodroot, Chamomile, Eucalyptus neem, tulsi, propolis, cocoa husk, pomegranate, cranberry etc. are being used widely these days. [42, 43] These products have shown to improve gingival and periodontal parameters without side effects.

6.4.1. Herbal Combinations: Along with individual herbs, herbal combinations can help to combat periodontitis symptoms and can improve the oral hygiene. [44] 6.5. Colloidal drug carriers include micelles, emulsions, liposomes and nanoparticles (nanospheres and nanocapsules). Liposomes and nanoparticles are largely used due to ease and simplicity of preparation.

Colloidal carriers increase the specificity towards tissues, improve the bioavailability of drugs and protect them against enzyme inactivation. [45] 6.6. Local delivery of growth factors: Platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and pyridinoline cross-linked carboxyterminal telopeptide of Type I collagen (ICTP) are mediators involved in mitogenesis, angiogenesis, bone turnover and are essential for wound regeneration of periodontal tissues. [46, 47] Fibroblast growth factor is effectively introduction in local drug delivery. To regenerate periodontal tissues, a sandwich membrane composed of a collagen sponge scaffold and gelatin microspheres containing basic fibroblast growth factor (bFGF) in a controlled-release system was developed.

[48] 6.7. Nanoparticles: The recent success of many polymeric depot delivery systems has encouraged further research to develop new systems for use in regional therapy. Nanoparticles, owing to their small size, penetrate *Corresponding Author: Dr Vaishali Ashtaputre

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Local drug delivery in periodontics: tactical entreaty regions that may be inaccessible to other delivery systems. They reduce the frequency of administration and provide uniform distribution of the active agent over an extended period. Various studies have assessed efficacy of nanoparticles in periodontal diseases. Namely, Dung et al using Antisense oligonucleotide- loaded chitosantripolyphosphate (TPP) nanoparticles, Pinon et al using Triclosan-loaded polymeric (PLGA, PLA and cellulose acetate phthalate) nanoparticles and Moulari et. al, using Harungana madagascariensis leaf (HLE)loaded PLGA nanoparticles. [23]

VII. CONCLUSION New formulations and novel-controlled delivery system will continue to be explored. One of the most persistent problems faced by the formulation technologist is that many drugs do not reach the target areas in the therapeutic concentrations intended. By the development of novel drug delivery systems, a more site-specified and controlled drug delivery systems was made possible, thereby dose and side effects can be reduced which ensures better patient compliance. There is no single universal drug that would be effective in all situations.

Therefore, at non-responsive sites, bacterial and antibiotic sensitivity testing may be necessary to determine putative pathogens and their susceptibility to specific antimicrobial agents. Local drug delivery systems usually do not provide a benefit beyond what is achievable with conventional scaling and root planing.

In conclusion, hence antimicrobial drug as site-specific dental formulations into periodontal pocket proves to be a viable alternative to conventional periodontal therapy. Obviously, its clinical use in the fastgrowing field is promising.

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*Corresponding Author: Dr Vaishali Ashtaputre

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